Cystic fibrosis (CF) is the most common lethal autosomal recessive disease among Caucasians, affecting nearly 1 in 2500 newborns. Boat et al., Metabolic Basis of Inherited Disease. (McGraw-Hill, N.Y. 1989) 2649-2680. CF is caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR), a 1480 amino acid protein which has been associated with the expression of chloride conductance in a variety of eukaryotic cell types. See Rommens et al., Science 245:1059 (1989); Riorden et al., Science 245:1066 (1989); Kerem et al., Science 245:1073 (1989); Drumm et al., Cell 64:681 (1991); Kartner et al., Cell 64:681 (1991); Gregory et al., Nature 347:382 (1990); Rich et al., Nature 347:358 (1990); Rommens et al., PNAS (USA) 88:7500 (1991). Defects in CFTR destroy or reduce the ability of epithelial cells in the airways, sweat glands, pancreas and other tissues to secret CI in response to cAMP-mediated agonists and impair activation of apical membrane channels by cAMP-dependent protein kinase A (PKA). See Frizell et al., Trends Neurosci 10:190 (1987); Welsh, FASEB J. 4:2718 (1990).
Although over 100 different mutations have been identified in the CFTR gene, a single NBF1 mutation, the deletion of phenylalanine 508 (.DELTA.F508), accounts for almost 70% of the CF alleles in the population. Kerem et al., Science 245:1073 (1989); The Cystic Fibrosis Genetic Analysis Consortium, Am. J. Hum. Genet. (1990). Patients homozygous for the .DELTA.F508 mutation present a similar clinical picture, including elevated sweat chloride levels, chronic pulmonary disease, and pancreatic insufficiency and are generally classified as severely affected. Kerem et al., N. Engl. J. Med. 323:1 51 7 (1990). The clinical profiles of patients carrying other mutations, however, show a broad spectrum of severity. Kerem et al., N. Engl. J. Med. 323:1517 (1990); Cutting et al., Nature 346:366 (1990); Osborne et al., Am. J. Hum. Genet. 48:608 (1990); White et al., Nature 344:665 (1990); Iannuzi et al., Am. J. Hum. Genet. 48:226 (1991).
Given the high incidence and devastating nature of this disease, the development of effective CF treatments is imperative. For any therapeutic approach to have a great impact on the CF population, it must also be effective in treating the , .DELTA.F508 mutation, since it is estimated that as many as 92% of CF patients carry at least one .DELTA.F508 allele. Kerem et al., N. Engl. J. Med. 323:1517 (1990).